The fast actions of the excitatory neurotransmitter glutamate are mediated by glutamate-gated ion channels (ionotropic Glu receptors). Metabotropic glutamate receptors (mGluRs) are coupled to second messenger pathways via G proteins and modulate glutamatergic and GABAergic neurotransmission. Of the eight different types of mGluRs (mGluR1-mGluR8), mGluR8 is a member of group III, which are generally located presynaptically and regulate neurotransmitter release. Because of their role in modulating excitatory neurotransmission, mGluRs are attractive targets for therapies aimed at treating anxiety disorders. Our preliminary data show increased measures of anxiety in the open field and elevated plus maze in 6-month- old C57BI6/J mice lacking mGluR8 (mGluR8-/-). Further, the specific mGluRS agonist (S)-3,4,- dicarboxyphenylglycine (DCPG) induced neuronal activity marker c-Fos in GABA-ergic inhibitory neurons in the central nucleus of the amygdala (CeA) and suppressed excitatory synaptic transmission in the bed nucleus of the stria terminalis (BNST), brain areas involved in the regulation of anxiety. The effects of mGluRS on measures of anxiety might be mediated by the neuropeptides corticotropin-releasing factor (CRF) and arginine vasopressin (AVP). The amygdala, BNST, ventral hippocampus, and lateral septum, express these neuropeptides implicated in the regulation of anxiety. Our preliminary data show mGluRS immunoreactivity in the amygdala and BNST of C57BI6/J wild-type mice. We hypothesize that mGluRS modulates measures of anxiety in the amygdaloid complex and that effects of mGiuRS signaling on the expression of CRF and AVP contribute to increased measures of anxiety in mGluR8-/- mice. The Specific Aims are: (1) To determine if mGluR8-/- mice show increased measures of anxiety; (2) To determine if acute stimulation of mGluR8 reduces measures of anxiety and alters expression of CRF and AVP in wild-type mice; (3) To localize mGluR8 in neural structures implicated in the regulation of anxiety; and (4) To determine the role of mGluR8 in synaptic function in the basolateral nucleus of the amygdala (BLA) and extended amygdala (BNST and CeA). Elucidating the role of mGluR8 in anxiety and assessing the potential of pharmacological mGluR8 stimulation to reduce anxiety might be especially valuable for patients with anxiety disorders resistant to treatment with benzodiazepine. [unreadable] [unreadable] [unreadable]